Biology subjects

Walter, C.

Publications and source records attributed to Walter, C..

14 recordsLinked to original sources

bioRxiv2026

Mapping the distribution of elms in Britain after a century of Dutch elm disease

The establishment of novel pests and pathogens that devastate populations of trees is increasing around the world, giving rise to policy and management decisions about how to restore treescapes. Such decisions may be informed by the example of Dutch elm disease (DED) which caused most mature elms in Europe and North America to be lost in the mid-20th Century. Although affected elms can regenerate, they succumb again after several years. Considerable effort has been made to restore elm through: (1) cloning and breeding of surviving local trees, (2) introduction of resistant Asiatic species, (3) introduction or production of hybrids bred from local and Asiatic species. As trees are planted out into the landscape, it is necessary to record them, and monitor their survival. Here, we compile and map 82,244 elm trees in Britain recorded as 269 distinct elm species, hybrids and cultivars. The vast majority of records are for surviving field elm, English elm and wych elm, which would grow again to maturity if the virulence of the pathogen could be attenuated. The most commonly planted elms were the hybrids: Nanguen (commercial name Lutece), followed by New Horizon, Ademuz, Lobel and Sapporo Autumn Gold, each of which had over 200 occurrences. The current elm-scape of Britain represents much restoration effort and contains considerable genetic diversity.

plant biology↗

bioRxiv2026

fourSynergy: Ensemble-based interaction calling on 4C-seq data using gradient-free optimization

MotivationChromatin organization plays a crucial role in gene regulation and is associated with various severe diseases like cancer. Since chromatin changes are potentially reversible, a deeper understanding of the alterations needs to be harnessed for the development of new therapies. Circular Chromosome Conformation Capture Sequencing (4C-seq) is a sequencing technique enabling the identification of chromatin interactions between genes and regulatory elements. This work aims to develop an ensemble algorithm that utilizes synergies among available 4C-seq tools, which in turn allows to achieve superior predictive performance in interaction calling. ResultsWe employed existing 4C-seq algorithms using a weighted-voting approach. By optimizing the tool weights according to various predictive metrics using gradient-free optimization strategies, we demonstrate the potential of combining multiple 4C-seq analysis tools for interaction calling. Our results indicate that a weighted-voting based ensemble approach can outperform individual algorithms in various datasets. Although the optimal solutions differ across the 4C-seq datasets, we successfully identified global solutions that outperform the individual algorithms for all datasets analyzed. Availabilityhttps://github.com/sophiewind/fourSynergy, https://github.com/sophiewind/fourSynergy_pip Contactsophie.wind@uni-muenster.de Supplementary informationSupplementary data are available at Journal Name online.

bioinformatics↗

bioRxiv2026

T-Rex: Standardized Analysis of Germline Variants in Whole-Exome Sequencing Trios

Whole-exome sequencing (WES) enables the identification of rare germline variants contributing to pediatric diseases. Trio-based sequencing, comparing affected children with their parents, is particularly effective for rare disease genetics. However, WES data analysis requires bioinformatics expertise, varies across institutions, and is often incompatible with clinical workflows. We developed T-Rex (Trio Rare variant analysis of EXomes), a cross-platform desktop application that enables the standardized and local analysis of WES germline Trio data without the need for programming knowledge. T-Rex integrates state-of-the-art tools for alignment, dual-variant calling (GATK HaplotypeCaller + VarScan2), annotation (SNPEff/SNPSift), rare-variant filtering based on population frequencies (gnomAD), and family-based statistical testing, including the Transmission Disequilibrium Test with multiple-testing correction. Benchmarking of the dual-caller strategy on the Genome in a Bottle Ashkenazim Trio demonstrates high precision (99.2%) while maintaining robust sensitivity (91.1%). User testing (n=13) confirmed quick learning across clinicians and researchers. Application to a cohort of n=121 pediatric cancer Trio datasets, filtering for rare protein-coding variants (MAF[≤]0.1% in gnomAD v4.0), validated all assessable previously reported pathogenic variants. Overall, T-Rex enables clinicians to robustly analyze WES Trio data in compliance with data protection regulations without requiring additional software licenses. As one of the first platforms for comprehensive WES Trio analysis that requires no programming expertise while providing clinical-grade, end-to-end workflows, T-Rex facilitates collaborative research between clinics and reduces reliance on external providers. Implementation and AvailabilityThe source code is available on GitHub (https://github.com/SaraLuisaReh/trex). The fully precompiled app is available on Zenodo (https://zenodo.org/records/19135262).

bioinformatics↗

bioRxiv2026

Renal adaptation to high salt diet requires tubular Na+ secretion through type A intercalated cells

BackgroundIn the context of increased salt intake in the world population, the understanding of the mechanisms that contribute to its correct renal excretion and therefore, avoid variation of blood volume and blood pressure is of major importance. MethodsMolecular, ex vivo microperfusion on isolated tubules, and integrative analysis, was used to identify, characterize and investigate a Na+ secretion pathway in the collecting duct. ResultsIn collecting duct of mice, salt load induced an increase of the type A intercalated cells (AIC) number, an overexpression of the H(Na),K-ATPase type 2 (HKA2) catalytic subunit Atp12a and a stimulation of the bumetanide-sensitive Na+ secretion in isolated and microperfused tubules. Surprisingly, HKA2KO mice fed a high-salt diet exhibit a strong dysregulation of their Na+ and water balance with a pronounced loss of Na+ and fluid, alkalosis, hypokalemia and low blood pressure. This Bartter-like phenotype is due to an over-inhibition of the thick ascending limb (TAL) related to an elevated PGE2 production. ConclusionOur findings establish that activation of Na+ secretion in AIC act as the fine-tuning knob in the regulation of renal Na+ excretion in response to high salt intake. Its absence is overcompensated by an inhibition of the Na+ transport system of the TAL.

physiology↗

bioRxiv2025

plinkQC: An Integrated Tool for Ancestry Inference, Sample Selection, and Quality Control in Population Genetics

MotivationPopulation genetic analyses rely on high quality datasets that pass rigorous controls for sample and marker quality. Many analyses also require additional processing including identification of ancestry and sample relatedness. A software package that addresses all these common, yet crucial tasks is missing. ResultsWe have developed plinkQC, an R/CRAN package that combines these functionalities into a single software package with detailed vignettes for example applications. plinkQC determines the ancestry of study samples via a pre-trained random forest classifier that reaches 98% performance accuracy with just 5% of marker overlap between reference and user data. To obtain the maximal set of unrelated study samples, we developed a graph-based pruning method, taking both relationship estimates and sample quality into account. We demonstrate optimal sample selection on the 1000 Genomes project, where we retain an additional 71 samples compared to publicly available exclusion lists. Finally, plinkQC bundles these results together with per-individual and per-marker quality control checks into three simple functions and returns both the quality controlled data set and quality control report about each step of the analysis. AvailabilityplinkQC is available as an R/CRAN package. The documentation and code are available on github: https://meyer-lab-cshl.github.io/plinkQC/ and https://github.com/meyer-lab-cshl/plinkQC_manuscript.

bioinformatics↗

bioRxiv2025

The nuclear receptor NR4A1 serves as a neutrophil-intrinsic regulator mitigating stroke severity

Ischemic stroke is accompanied by recruitment and activation of immune cells which play an important role in the progression of the brain damage. The nuclear receptor NR4A1 emerged as a key regulator within the inflammatory response of several immune diseases by regulating immune cell activation. In this study, we investigated the role of NR4A1 in the activation and recruitment of brain resident and peripheral immune cells after cerebral ischemia. Here, we show that NR4A1 mediates an anti-inflammatory and damage-limiting effect after stroke. This effect is largely mediated by neutrophil recruitment and importantly, NR4A1 activation with its ligand Cytosporone B improves functional outcome and reduces brain damage. Modulation of NR4A1 is therefore a promising therapeutic target for the treatment of the nuclear receptor NR4A1 in the activation and recruitment of peripheral and brain resident immune cells after cerebral ischemia and its consequences for stroke outcome. We demonstrate that NR4A1 ablation augments neutrophil activation and CNS recruitment within days after stroke thereby increasing infarct size, CNS inflammation, neuronal damage and deteriorating functional outcome. This effect is mediated via modulation of cell-intrinsic neutrophil function and maturation as illustrated by neutrophil-specific NR4A1 ablation and mixed bone-marrow chimera experiments. Notably, the NR4A1 agonist Cytosporone B reduced CNS neutrophil infiltration, infarct size and functional outcome after stroke in a bicentric preclinical stroke trial, demonstrating that NR4A1-mediated control of neutrophil reactivity is amenable to pharmacological modulation. In humans, NR4A1 expressing neutrophils are present in the peripheral blood of stroke patients and neutrophil NR4A1 expression correlates with improved long-term outcome after 3 months. Furthermore, NR4A1 expression in brain parenchyma neutrophils is negatively correlated with neuronal cell loss, illustrating a role of NR4A1 in regulating neutrophil mediated neuronal cell death in human stroke. Together our data reveal the nuclear factor NR4A1 as a brake of intrinsic neutrophil activity controlling neutrophil-mediated brain inflammation and neurotoxicity in stroke which may serve as a novel therapeutic target to limit inflammation-associated augmentation of ischemic damage after stroke.

neuroscience↗

bioRxiv2024

The Mitochondrial Brown Adipose Tissue Maintenance Factor Nipsnap1 Interfaces Directly with the Beta-Oxidation Protein Machinery.

BackgroundThe activation of brown adipose tissue (BAT) is associated with improved metabolic health in humans. We previously identified the mitochondrial protein 4-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like 1 (Nipsnap1) as a novel regulatory factor that integrates with lipid metabolism and is critical to sustain the long-term activation of BAT, but the precise mechanism and function of Nipsnap1 is unknown. ObjectivesDefine how the regulatory factor Nipsnap1 integrates with lipid metabolism. MethodsWe generated adeno-associated viral (AAV) constructs that overexpress Nipsnap1 in the thermogenic fat of mice. We then measured both whole-body and cellular mitochondrial metabolism and mapped the first Nipsnap1 interacting protein-protein network. ResultsHerein, we show that adipose-specific overexpression of Nipsnap1 in mice increases energy expenditure through the utilization of lipids as an energy substrate. The increase in energy expenditure results in reduced weight gain. Additionally, we show that Nipsnap1 overexpression in primary adipocytes increases lipid beta-oxidation. Moreover, we mapped the first protein- protein network of Nipsnap1 in brown adipocytes and show that Nipsnap1 interacts with proteins that regulate both peroxisomal and mitochondrial fatty acid beta-oxidation. ConclusionThis study elucidates a mechanistic function of Nipsnap1 in thermogenic fat where Nipsnap1 facilitates a functional connection between peroxisomal and mitochondrial beta-oxidation pathways. By enhancing lipid utilization as energy substrates, Nipsnap1 plays a pivotal role in sustaining thermogenic fat activation to increase energy expenditure. These findings underscore the potential of Nipsnap1 as a therapeutic target for metabolic health.

cell biology↗

bioRxiv2024

Small molecule oxybutynin rescues proliferative capacity of complex III-defective MPCs

Mitochondrial disease encompasses a group of genetically inherited disorders hallmarked by an inability of the respiratory chain to produce sufficient ATP. These disorders present with multisystemic pathologies that predominantly impact highly energetic tissues such as skeletal muscle. There is no cure or effective treatment for mitochondrial disease. We have discovered a small molecule known as oxybutynin that can bypass Complex III mitochondrial dysfunction in primary murine and human skeletal muscle progenitor cells (MPCs). Oxybutynin administration improves MPC proliferative capacity, enhances cellular glycolytic function, and improves myotube formation. Mechanistically, results from our isothermal shift assay indicates that oxybutynin interacts with a suite of proteins involved in mRNA processing which then trigger the upregulation biological pathways to circumvent CIII mitochondrial dysfunction. Taken together, we provide evidence for the small molecule oxybutynin as a potential therapeutic candidate for the future treatment of CIII mitochondrial dysfunction.

cell biology↗

bioRxiv2024

AQP1- A regulatory factor associated with brown adipose tissue silencing

The activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) by environmental cold challenge yields strong metabolic benefit in the face of diet-induced obesity (DIO). Yet, a critical barrier to leveraging brown fat NST for therapeutic use against metabolic disease is that BAT is silenced and inactive at physiological ambient temperature conditions in humans. The mechanisms that govern this silencing process remain poorly understood. Here, we identified a putative BAT-silencing factor, aquaporin-1 (AQP1), in brown fat from wild-type (WT) mice via proteomics analysis. We generated the first BAT-specific AQP1 knockout mice (AQP1-KO) and revealed that AQP1-KO could activate NST under BAT silencing environmental conditions and that the AQP1-KO mice were significantly protected against DIO and metabolic dysfunction compared to Flox controls. We found that AQP1-KO mice on high fat diet (HFD) had reduced weight gain through reductions in fat mass, improved glucose tolerance, and increased whole body energy expenditure compared to Flox control mice. Mechanistically, we show that AQP1 ablation in mice had upregulated gene expression related to the electron transport chain (ETC) and mitochondrial translation contributing to the activation of NST under BAT environmental silenced conditions. Significance StatementNovel strategies to combat obesity-associated metabolic dysfunction are urgently needed to curb the growing obesity epidemic. Investigation of brown adipose tissue (BAT) silencing mechanisms may reveal novel therapeutic targets that when ablated, can activate BAT to increase energy expenditure and protect subjects against the metabolic dysfunction associated with obesity. We have identified Aquaporin 1 (AQP1) as a putative BAT silencer regulatory factor and show through the generation of the first BAT-specific aquaporin-1 knockout (AQP1-KO) mouse that BAT can be activated under environmental silencing conditions. We further show that these mice are protected against diet-induced obesity, with improved glucose tolerance, and increased energy expenditure. These findings highlight AQP1 as a promising therapeutic target in the emerging research field of BAT silencers.

molecular biology↗

bioRxiv2024

Microvascular immunity is organ-specific and concealed in peripheral blood

Blood tests are a common method for diagnosing and monitoring various health conditions. Nevertheless, the extent to which phlebotomy can offer insights into immune and organ dysfunction remains uncertain. Here, we conducted a comprehensive analysis of blood-borne leukocytes in the microvasculature of different mouse organs and compared it to peripheral blood and parenchymal samples. We observed that microvascular immune cells outnumber tissue-resident counterparts in the kidney, liver and lung. Classical monocytes and lymphocytes are diminished while nonclassical and SSC-high monocytes are enriched compared to blood. Utilizing single-cell sequencing, we identified specific cell populations up to 100-fold expanded in the kidney vasculature including macrophages, plasmacytoid dendritic cells, B cells, and innate lymphoid cells type 2. Microvascular enrichment could trigger a local phenotype switch as shown in glomerulus-restricted B cells. Peritonitis and acute kidney injury (AKI) elicited a multifaceted and systemic response of microvascular leukocytes. It involved remote organ effects, such as a 16-fold increase of leukocytes in the splenic circulation or 64-fold increase of SSC-high monocytes in the liver circulation that was not detectable in the peripheral blood or the tissue. Following full recovery from AKI, persistent and complex changes were observed predominantly in the renal vasculature, while most leukocytes in the peripheral blood had already returned to baseline levels. Collectively, our findings suggest a paradigm of organ- and disease-specific microvascular immunity that largely eludes conventional blood and tissue analysis.

immunology↗

bioRxiv2024

PuMA: PubMed Gene-Celltype-Relation Atlas

Rapid extraction and visualization of cell-specific gene expression is important for automatic celltype annotation, e.g. in single cell analysis. There is an emerging field in which tools such as curated databases or Machine Learning methods are used to support celltype annotation. However, complementing approaches to efficiently incorporate latest knowledge of free-text articles from literature databases, such as PubMed are understudied. This work introduces the PubMed Gene/Celltype-Relation Atlas (PuMA) which provides a local, easy-to-use web-interface to facilitate automatic celltype annotation. It utilizes pretrained large language models in order to extract gene and celltype concepts from Pub-Med and links biomedical ontologies to suggest gene to celltype relations. It includes a search tool for genes and cells, additionally providing an interactive graph visualization for exploring cross-relations. Each result is fully traceable by linking the relevant PubMed articles. The software framework is freely available and enables regular article imports for incremental knowledge updates. GitLab: imigitlab.uni-muenster.de/published/PuMA

bioinformatics↗

bioRxiv2022

GDF15 mediates renal cell plasticity in response to potassium depletion

A low potassium (K+) intake is a common situation in the population of the Westernized countries where processed food is prevalent in the diet. Here, we show that expression of GDF15, a TGF{beta}-related growth factor, is increased in renal tubular segments and gut parts of mice in response to low-K+ diet leading to a systemic elevation of its plasma and urine concentration. In human, under mild dietary K+ restriction, we observed that urine GDF15 excretion is correlated with plasma K+ level. Conversely to WT mice, adaptation to K+ restriction of GDF15-KO mice is not optimal, they do not increase their number of type A intercalated cell, responsible for K+ retention, and have a delayed renal K+ retention, leading to early development of hypokalemia. This renal effect of GDF15 depends on ErBb2 receptor, whose expression is increased in the kidney collecting ducts. We also observe that, in the absence of GDF15, the release of K+ by the muscles is blunted which is compensated by a loss of muscle mass. Thus, in this study, we showed that GDF15 plays a central role in the response to K+ restriction by orchestrating the modification of the cell composition of the collecting duct.

physiology↗

bioRxiv2022

Multiscale obstruction sensitivity in collective cell migration

Cellular forces and intercellular cooperation generate collective cell migration. Pathological changes in cell-level genetic and physical properties cause jamming, unjamming, and scattering in epithelial migration. Separately, changes in microenvironment stiffness and confinement can produce varying modes of cell migration. However, it remains unclear whether and how mesoscale disruptions in matrix topology alter collective cell migration. To address this question, we microfabricated matrices with stumps of defined geometry, density, and orientation, which serve as obstructions in the path of collectively migrating healthy mammary epithelial cells. Here, we show that cells lose their speed and directionality when moving through dense obstructions, compared to those sparsely spaced. On flat surfaces, leader cells are significantly stiffer than follower cells, while dense obstructions lead to the overall softening of cells. In moving through dense obstructions, epithelial cells lose the sense of leaders and followers in their physical properties, migration phenotypes, and fluidity. Although Rac inhibition reduces obstruction sensitivity, loss of cell-cell cooperation and induction of leader-like phenotype via -catenin depletion eliminates the effect of matrix obstructions on epithelial migration. Through a lattice-based model, we identify cellular protrusions, polarity, and leader-follower communication as key mechanisms for obstruction-sensitive collective cell migration. Together, microscale cytoskeletal response, mesoscale softening and disorder, and macroscale multicellular communication enable epithelial cell populations to sense topological obstructions encountered in challenging environments. These results reveal that cohesive, healthy populations are more obstruction sensitive than the dysfunctional, aggressive ones. The obstruction-sensitivity could add to the emerging disease mechanotypes such as cell stiffness and traction forces.

biophysics↗

bioRxiv2021

A new variant of ASIC2 mediates sodium retention in nephrotic syndrome

Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal Na retention leading to oedema. This Na retention is usually attributed to epithelial sodium channel (ENaC) activation following plasma aldosterone increase. However, most nephrotic patients show normal aldosterone levels. Using a corticosteroid-clamped rat model of INS (CC-PAN), we showed that the observed electrogenic and amiloride-sensitive Na retention could not be attributed to ENaC. We, then, identified a truncated variant of acid sensing ion channel 2b (ASIC2b) that induced sustained acid-stimulated sodium currents when co-expressed with ASIC2a. Interestingly, CC-PAN nephrotic ASIC2b-null rats did not develop sodium retention. We finally showed that expression of the truncated ASIC2b in kidney was dependent on the presence of albumin in the tubule lumen and activation of ERK in renal cells. Finally, the presence of ASIC2 mRNA was also detected in kidney biopsies from patients with INS but in any of the patients with other renal diseases. We have, therefore, identified a novel variant of ASIC2b responsible for the renal Na retention in the pathological context of INS.

pathology↗